Metabolomics: Taking Aim at Diabetic Kidney Failure
Posted on by Dr. Francis Collins
My own research laboratory has worked on the genetics of diabetes for two decades. One of my colleagues from those early days, Andrzej Krolewski, a physician-scientist at the Joslin Diabetes Center in Boston, wondered why about one-third of people with type 2 diabetes eventually develop kidney damage that progresses to end-stage renal disease (ESRD), but others don’t. A stealthy condition that can take years for symptoms to appear, ESRD occurs when the kidneys fail, allowing toxic wastes to build up. The only treatments available are dialysis or kidney transplants.
It is known that rising levels of the protein albumin in the urine are a sign of kidney damage, but that seems to happen rather late in the process. So, Krolewski and his Joslin colleagues set about searching for better ways of predicting which people with diabetes are at risk for ESRD: information that could be used to develop new approaches to diagnosing, treating, and possibly even preventing this life-threatening complication.
In 1992, with NIH funding, the Joslin Study of the Genetics of Kidney Complications was launched; this was a prospective study in which relatively healthy volunteers with a recent diagnosis of type 2 diabetes were followed over the course of eight to 12 years. As part of the study, researchers periodically drew blood from participants and tracked their health status, hoping this information might someday prove useful in identifying markers in the blood associated with ESRD risk.
Now fast-forward to 2013. Monika Niewczas and others in Krolewski’s lab applied a more comprehensive approach to blood analysis called metabolomics, allowing sampling of a wide array of molecules.
The Joslin researchers used a device called a mass spectrometer to look for levels of about 2,400 metabolites in blood samples from two groups of volunteers: 40 who had developed ESRD over the course of the study and 40 who had not. The researchers found that the first group had higher levels of 78 metabolites known to be elevated in ESRD than the second group. More importantly, 16 of these 78 metabolites were already elevated in the first group’s blood at the outset of the study—years before their first signs of ESRD appeared. Among the metabolites most strongly associated with progression to ESRD were urate; a couple of phenyl compounds known to accumulate when kidney function declines; myo-inositol, a molecule involved in insulin signaling and a great many other biological processes; and pseudouridine, a molecule that is an indicator of RNA turnover in the body. These results were surprising because, until now, such metabolites were thought to accumulate only in late stages of the disease.
It remains to be determined whether these 16 metabolites are early biomarkers of kidney failure or might actually be contributing directly to the disease process. Additional work is also needed to assess the implications of the new findings for type 1 diabetes. To that end, the Joslin scientists and others are conducting genetic studies [2, 3] to explore whether there are some people with type 1 diabetes who are more susceptible to ESRD than others.
 Uremic solutes and risk of end-stage renal disease in type 2 diabetes: metabolomic study. Niewczas MA, Sirich TL, Mathew AV, Skupien J, Mohney RP, Warram JH, Smiles A, Huang X, Walker W, Byun J, Karoly ED, Kensicki EM, Berry GT, Bonventre JV, Pennathur S, Meyer TW, Krolewski AS. Kidney Int. 2014 Jan 15.
 Chromosome 2q31.1 associates with ESRD in women with type 1 diabetes. Sandholm N, McKnight AJ, Salem RM, Brennan EP, Forsblom C, Harjutsalo V, Mäkinen VP, McKay GJ, Sadlier DM, Williams WW, Martin F, Panduru NM, Tarnow L, Tuomilehto J, Tryggvason K, Zerbini G, Comeau ME, Langefeld CD; FIND Consortium, Godson C, Hirschhorn JN, Maxwell AP, Florez JC, Groop PH; FinnDiane Study Group and the GENIE Consortium. J Am Soc Nephrol. 2013 Oct;24(10):1537-43.
 Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes. Pezzolesi MG, Poznik GD, Mychaleckyj JC, Paterson AD, Barati MT, Klein JB, Ng DP, Placha G, Canani LH, Bochenski J, Waggott D, Merchant ML, Krolewski B, Mirea L, Wanic K, Katavetin P, Kure M, Wolkow P, Dunn JS, Smiles A, Walker WH, Boright AP, Bull SB; DCCT/EDIC Research Group, Doria A, Rogus JJ, Rich SS, Warram JH, Krolewski AS. Diabetes. 2009 Jun;58(6):1403-10.
Andrzej Krolewski, Section on Genetics and Epidemiology, Joslin Diabetes Center, Boston
End-stage kidney disease (MedlinePlus/NIH)
Kidney Disease Statistics for the United States (NIDDK/NIH Information Clearinghouse)
NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases
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